In VitroAmyloid Fibril Formation by Synthetic Peptides Corresponding to the Amino Terminus of apoSAA Isoforms from Amyloid-Susceptible and Amyloid-Resistant Mice

Kirschner, Daniel A.; Elliott-Bryant, Rosemary; Szumowski, K.; Gonnerman, Wayne A.; Kindy, Mark S.; Sipe, Jean D.; Cathcart, Edgar S.

doi:10.1006/jsbi.1998.4047

Cited by 34 publications

(17 citation statements)

References 47 publications

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“…This interpretation is consistent with the fact that three out of the six amino acid differences between SAA2.2 and SAA1.1 are located at the N-terminus (Figure 1), and with previous studies showing that the N-terminus of SAA comprises the amyloid-determining region [16,17,20,46]. Interestingly, it was reported that a peptide consisting of the N-terminal 11 residues of SAA2.2 was also capable of forming fibrillar-like aggregates [17], further supporting our conclusion that the N-terminus plays an important role in SAA2.2 amyloid formation in vitro.…”

Section: Saa22 Can Form Amyloid Fibrils In Vitrosupporting

confidence: 89%

“…Comparison of the amino acid sequences of SAA1.1 with the amyloid resistant SAA2.1 and 2.2 isoforms reveal 91 and 94% sequence identity, respectively ( Figure 1). The most significant differences are located at the N-terminus, consistent with several studies showing that the N-terminus of SAA consists of the amyloidogenic [16,17] and lipid-binding [18][19][20][21] region. Because of the high content of a-helical structure in SAA [18,22,23], it is clear that SAA amyloid formation must involve a conformational change accompanied by a significant increase in b-sheet structure.…”

Section: Introductionsupporting

confidence: 88%

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From hexamer to amyloid: Marginal stability of apolipoprotein SAA2.2 leads toin vitrofibril formation at physiological temperature

Wang

Lashuel

Colón

2005

Amyloid

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Serum amyloid A (SAA) is a major acute phase reactant and a small apolipoprotein of high density lipoproteins (HDL) in the serum. In cases of prolonged inflammation, SAA may form amyloid fibrils, leading to the disease of amyloid A (AA) amyloidosis. Recently, we have shown that murine SAA2.2, a non-amyloidogenic isoform in vivo, forms a hexamer in vitro containing a putative central channel. It is reported herein that upon thermal denaturation, hexameric SAA2.2 irreversibly dissociates to a misfolded monomer at physiological temperature, formation of which coincides with a significant loss of alpha-helical and gain of beta-sheet structure. When SAA2.2 is incubated for several days at 37 degrees C, sedimentation analytical ultracentrifugation reveals the presence of soluble high molecular weight aggregates, which upon further incubation undergo subsequent self-assembly into amyloid fibrils. Limited proteolysis experiments suggest that the in vitro amyloidogenecity of SAA2.2 is related to structural alteration in its N-terminus. Our observation that SAA2.2 can form amyloid fibrils in vitro at physiological temperatures suggests that SAA2.2's inability to cause amyloidosis may be related to other factors, such as the stabilization of hexameric SAA2.2 (possibly through ligand binding), and/or the slow kinetics of aberrant misfolding and self-assembly.

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Section: Saa22 Can Form Amyloid Fibrils In Vitrosupporting

confidence: 89%

Section: Introductionsupporting

confidence: 88%

From hexamer to amyloid: Marginal stability of apolipoprotein SAA2.2 leads toin vitrofibril formation at physiological temperature

Wang

Lashuel

Colón

2005

Amyloid

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“…Normally, the N-terminal amyloidogenic portion of SAA is bound to high-density lipoprotein (HDL), and thus protected from interaction with AA fibrils (36). However, when the serum concentration of this amyloidogenic protein is greatly increased as a result of an inflammatory stimulus, not all SAA molecules are bound to HDL (37), and thus would be free to interact with AA-derived fibril seeds.…”

Section: Discussionmentioning

confidence: 99%

Transmissibility of systemic amyloidosis by a prion-like mechanism

Lundmark

Westermark

Nyström

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

249

213

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3T3-L1 adipocytes were incubated in serum-free media at 37°C with (dashed line) or without (solid line) 100 ng͞ml insulin for 8 h. Isoproterenol (10 M) was then added for the indicated time course at 37°C, and intracellular cAMP was determined by enzyme immunoassay, as described in Materials and Methods. Data are from a typical experiment done in triplicate wells Ϯ SEM and are representative of three separate experiments. (B) 3T3-L1 adipocytes were incubated in serum-free media for 8 h. Where indicated, 100 ng͞ml insulin was added for 15 min before isoproterenol treatment. Cells were then treated with 10 M isoproterenol for 5 min at 37°C, and intracellular cAMP was determined by enzyme immunoassay, as described in Materials and Methods. Data are from a typical experiment done in triplicate wells Ϯ SEM and are representative of three separate experiments.www.pnas.org͞cgi͞doi͞10.1073͞pnas.0630528100 After this, cells were treated with 10 M isoproterenol for 5 min at 37°C. Cells were then washed with PBS at 37°C and restimulated with a second 10 M dose of isoproterenol for an additional 5 min at 37°C; intracellular cAMP was determined by enzyme immunoassay. (B) 3T3-L1 adipocytes were incubated at 37°C in serum-free media for 8 h in the presence (dashed lines) or absence (solid lines) of 100 ng͞ml insulin. Forskolin was added for the final 5 min, and intracellular cAMP levels were determined by enzyme-linked immunoassay. Data are from typical experiments done in triplicate wells and are representative of three separate experiments.

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“…There are a variety of biological and designed proteins that, similarly to our model peptides, self-assemble into twisted amyloid ␤-sheet polymers typically 5-10 nm in diameter (7,8,(19)(20)(21)(22), e.g., characterizing Alzheimer's and prion diseases, and of the de novo ␤-sandwich protein betabellin 15D (23). The scheme (Fig.…”

Section: Resultsmentioning

confidence: 99%

Hierarchical self-assembly of chiral rod-like molecules as a model for peptide β-sheet tapes, ribbons, fibrils, and fibers

Aggeli

Nyrkova²,

Bell³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

1,023

1,051

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A generic statistical mechanical model is presented for the selfassembly of chiral rod-like units, such as ␤-sheet-forming peptides, into helical tapes, which with increasing concentration associate into twisted ribbons (double tapes), fibrils (twisted stacks of ribbons), and fibers (entwined fibrils). The finite fibril width and helicity is shown to stem from a competition between the free energy gain from attraction between ribbons and the penalty because of elastic distortion of the intrinsically twisted ribbons on incorporation into a growing fibril. Fibers are stabilized similarly. The behavior of two rationally designed 11-aa residue peptides, P 11-I and P11-II, is illustrative of the proposed scheme. P11-I and P11-II are designed to adopt the ␤-strand conformation and to selfassemble in one dimension to form antiparallel ␤-sheet tapes, ribbons, fibrils, and fibers in well-defined solution conditions. The energetic parameters governing self-assembly have been estimated from the experimental data using the model. The 8-nm-wide fibrils consist of eight tapes, are extremely robust (scission energy Ϸ200 kBT), and sufficiently rigid (persistence length lfibril Ϸ 20 -70 m) to form nematic solutions at peptide concentration c Ϸ 0.9 mM (volume fraction Ϸ0.0009 vol͞vol), which convert to self-supporting nematic gels at c > 4 mM. More generally, these observations provide a new insight into the generic self-assembling properties of ␤-sheet-forming peptides and shed new light on the factors governing the structures and stability of pathological amyloid fibrils in vivo. The model also provides a prescription of routes to novel macromolecules based on a variety of self-assembling chiral units, and protocols for extraction of the associated energy changes.P rospects for the large-scale production of low-cost peptides by genetic engineering (1) open up new opportunities for exploiting protein-like self-assembly as a route to novel biomolecular materials (2-5). In this context, the small-oligopeptide route has distinct processing advantages over the use of longer polypeptides. Previously, we have demonstrated that oligopeptides can be designed to self-assemble into micrometer-long ␤-sheet tapes (6). We now wish to show that, as a consequence of the amino acid chirality, an entire hierarchy of twisted self-assembling macromolecular structures is accessible, with tapes as the most primitive form: ribbons, fibrils, and fibers. These polymers are shown to give rise to nematic fluids and gels at concentrations determined by the characteristic flexibility and length of each type of polymer.The type of molecular assembly we discuss and exemplify here arises not only in the context of desirable engineered biomaterials, but also in pathological self-assembly of mis-folded proteins, when the aggregated assemblies are referred-to as ''amyloids.'' A very wide class of proteins may be induced into producing the tapefibril-fiber sequence of structures (7) We present a theoretical model that enables the morphology and properties of thes...

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In VitroAmyloid Fibril Formation by Synthetic Peptides Corresponding to the Amino Terminus of apoSAA Isoforms from Amyloid-Susceptible and Amyloid-Resistant Mice

Cited by 34 publications

References 47 publications

From hexamer to amyloid: Marginal stability of apolipoprotein SAA2.2 leads toin vitrofibril formation at physiological temperature

From hexamer to amyloid: Marginal stability of apolipoprotein SAA2.2 leads toin vitrofibril formation at physiological temperature

Transmissibility of systemic amyloidosis by a prion-like mechanism

Hierarchical self-assembly of chiral rod-like molecules as a model for peptide β-sheet tapes, ribbons, fibrils, and fibers

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